PDF(Pubmed)
Abstract：
Hutchinson-Guilford Progeria syndrome (HGPS) is a rare genetic disease of premature aging and early death due to cardiovascular disease. The arteries of HGPS children and mice are pathologically stiff, and HGPS mice also display reduced arterial contractility. We recently showed that reduced contractility is an early event in HGPS and linked to an aberrantly low expression of smooth muscle myosin heavy chain (smMHC). Here, we have explored the basis for reduced smMHC abundance and asked whether it is a direct effect of progerin expression or a longer-term adaptive response. Myh11, the gene encoding for smMHC, is regulated by myocardin-related transcription factors (MRTFs), and we show that HGPS aortas have a reduced MRTF signature. Additionally, smooth muscle cells (SMCs) isolated from HGPS mice display reduced MRTF nuclear localization. Acute progerin expression in WT SMCs phenocopied both the decrease in MRTF nuclear localization and expression of Myh11 seen in HGPS. Interestingly, RNA-mediated depletion of MRTF-A in WT SMCs reproduced the preferential inhibitory effect of progerin on Myh11 mRNA relative to Acta2 mRNA. Our results show that progerin expression acutely disrupts MRTF localization to the nucleus and suggest that the consequent decrease in nuclear coactivator activity can help to explain the reduction in smMHC abundance and SMC contractility seen in HGPS.
摘要：
Hutchinson-GuilfordProgeria综合征（HGPS）是一种罕见的遗传性疾病，由于心血管疾病而导致过早衰老和过早死亡。HGPS儿童和小鼠的动脉在病理上僵硬，和HGPS小鼠也显示降低的动脉收缩力。我们最近表明，收缩性降低是HGPS的早期事件，并与平滑肌肌球蛋白重链（smMHC）的异常低表达有关。这里,我们已经探索了降低smMHC丰度的基础,并询问了这是早衰蛋白表达的直接作用还是长期适应性反应.Myh11，编码smMHC的基因，受肌钙蛋白相关转录因子（MRTF）调节，我们显示HGPS主动脉具有减少的MRTF特征。此外,从HGPS小鼠分离的平滑肌细胞（SMC）显示出减少的MRTF核定位。WTSMCs中的急性孕激素表达表型证实了MRTF核定位的减少和HGPS中Myh11的表达。有趣的是,WTSMC中RNA介导的MRTF-A耗竭再现了早衰蛋白相对于Acta2mRNA对Myh11mRNA的优先抑制作用。我们的结果表明，早老素的表达会严重破坏MRTF在细胞核中的定位，并表明核共激活因子活性的降低可以帮助解释在HGPS中看到的smMHC丰度和SMC收缩性的降低。
